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Stabilized compositions containing epidermal growth factor

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US4717717A
US4717717A US06927627 US92762786A US4717717A US 4717717 A US4717717 A US 4717717A US 06927627 US06927627 US 06927627 US 92762786 A US92762786 A US 92762786A US 4717717 A US4717717 A US 4717717A
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growth
factor
epidermal
cellulose
containing
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Amy L. Finkenaur
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Ethicon Inc
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Ethicon Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18Growth factors; Growth regulators
    • A61K38/1808Epidermal growth factor [EGF] urogastrone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L17/00Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/005Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters containing a biologically active substance, e.g. a medicament or a biocide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412Tissue-regenerating or healing or proliferative agents
    • A61L2300/414Growth factors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/808Materials and products related to genetic engineering or hybrid or fused cell technology, e.g. hybridoma, monoclonal products
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827Proteins from mammals or birds
    • Y10S530/834Urine; urinary system
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827Proteins from mammals or birds
    • Y10S530/854Glands

Abstract

Medicinal compositions containing epidermal growth factor are stabilized against loss of biological activity in the presence of moisture by including in said compositions a stabilizing amount of water-soluble cellulose polymer, preferably methylcellulose or a hydroxy alkylcellulose such as hydroxypropyl methylcellulose.

Description

The invention relates to a means for stabilizing compositions containing epidermal growth factors.

BACKGROUND OF THE INVENTION

Epidermal growth factor is a polypeptide material that has mitogenic activity for a number of kinds of cells, including epithelial and mesenchymal cells. Epidermal growth factor exhibits epidermal growth promoting activity and gastric acid secretion inhibiting activity, and is therefore useful as a medicament. It has been found that epidermal growth factor loses biological activity in the presence of moisture. This is disadvantageous because such loss of activity makes it impractical to store aqueous preparations of epidermal growth factor for extended periods of time. This invention provides a means for reducing the loss of activity of epidermal growth factor in the presence of moisture.

BRIEF SUMMARY OF THE INVENTION

The invention provides a means for stabilizing medicinal compositions containing epidermal growth factor against loss of biological activity in the presence of moisture which comprises incorporating in said compositions a water-soluble cellulose polymer such as hydroxypropyl methylcellulose and methylcellulose.

THE PRIOR ART

Errede et al., in U.S. Pat. No. 4,373,519, disclose a wound dressing including an absorbent such as cellulose material (which may be carboxymethyl-cellulose), wherein the wound dressing may contain various medicaments such as epidermal growth factor.

Hess et al. in U.S. Pat. No. 3,923,599, disclose plant enzyme formulations which may include a cellulose derivative.

Straub, in U.S. Pat. No. 3,927,209, discloses a para-influenza-3-virus composition that may include methylcellulose as a dispersing agent.

Dworschack et al., in U.S. Pat. No. 3,933,588, disclose enzymes immobilized on a cellulose derivative (DEAE cellulose) containing a quaternary ammonium compound as a stabilizer.

Diehl et al., in U.S. Pat. No. 4,011,169 disclose an enzyme-containing detergent composition containing an aminated starch or cellulose as a stabilizer.

Straub, in U.S. Pat. No. 4,188,375, discloses aqueous vaccine preparations that may contain methylcellulose as a dispersing agent. "Polysaccharides" are disclosed as "stabilizers", but it is not disclosed for what instability problem the stabilizers are added.

Akagi et al., in European Patent Application No. 0 150 067, disclose gamma-interferon stabilized with dextran or hydroxyethyl starch.

Jacobsen et al., in U.S. Pat. No. 4,540,506, disclose drain-cleaning formulations containing enzymes, which may contain hydroxyethyl cellulose as a thickener.

Arakawa and Timasheff, in Biochemistry 1982, Vol. 21, pages 6536-6544, disclose the use of sugars to stabilize proteins in aqueous media.

DETAILED DESCRIPTION OF THE INVENTION

The invention resides in the provision of stabilized compositions containing epidermal growth factor, preferably, human epidermal growth factor ("hEGF"). Epidermal growth factor and hEGF are known compositions that are either isolated from natural sources or are produced using recombinant DNA techniques. The following references describe epidermal growth factor, hEGH, and/or processes for isolating them from natural sources or producing them from rDNA techniques:

Camble et al., U.S. Pat. No. 3,914,824

Cohen et al., U.S. Pat. No. 3,948,875

Nishimura et al., U.S. Pat. No. 4,528,186

Bell, Published PCT patent application WO 85/00369

Urdea et al., Proc. Natl. Acad. Sci. USA 80, 7461-7465 (1983)

Hollenberg, "Epidermal Growth Factor-Urogastrone, A Polypeptide Acquiring Hormonal Status", Acad. Press, Inc., N.Y. (1979) pp. 90-132

Carpenter, "Epidermal Growth Factor" in: Handbook of Experimental Pharmacology, Vol. 57, Baserga, ed.

Lawn et al., "Cell" (1978) 15: 1157-1174

Savage et al., "J. Biol. Chem." (1972) 247: 7612-7621

As used in this application, "epidermal growth factor" is intended to include the class of polypeptides that have biological activity similar to that exhibited by natural human epidermal growth factor protein as measured in recognized bioassays such as the epidermal growth factor receptor binding assay described hereinbelow, and which have certain conserved amino acid residues and common positioning of disulfide bonds, as discussed by Carpenter et al. in "Epidermal Growth Factor, Its Receptor, and Related Proteins", Experimental Cell Research 164, (1986) 1-10. Thus, "epidermal growth factor" factor includes the hEGF produced by recombinant DNA techniques described by Bell, op. cit. supra, mouse EGF ("mEGF") isolated from the submaxillary glands of mice (see, for example, Cohen et al., op. cit. supra), rat EGF, natural human epidermal growth factor, which may be isolated from human urine as described by Nishimura et al., op. cit. supra, alpha-transforming growth factor, vaccinia growth factor, and bioactive derivatives and related polypeptides of any of the foregoing, including precursors that are transformed into active epidermal growth factor in situ by proteolytic processing. Human epidermal growth factor, including hEGF produced by recombinant DNA techniques, is preferred for use in the invention.

The stabilizers that are used in the invention are water-soluble cellulose derivatives such as methylcellulose. hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. Methylcellulose and the hydroxyalkyl cellulose derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methylcellulose are preferred.

The compositions that are stabilized in accordance with the invention are compositions containing epidermal growth factor, either in an aqueous medicinal composition such as a gel, solution, suspension, or dispersion, in which is dissolved an effective amount of the water-soluble cellulose derivative, or a lyophilized or other dehydrated derivative thereof which can be reconstituted by the addition of water. The exact amount of the cellulose derivative to be used in specific cases will vary, depending on factors such as presence or absence of other materials in the formulation, specific nature of the particular epidermal growth factor used, concentration of the epidermal growth factor, type of formulation, and the like. Expressed in terms of an aqueous formulation containing epidermal growth factor (either an initial formulation or a formulation that has been reconstituted following dehydration), the effective amount of the cellulose derivative will usually be at least 0.05 weight percent, based on weight of the whole composition. The maximum amount used is not at all critical, and will be in part determined by the type of formulation. For instance, an aqueous eye drop formulation will usually use an amount of the cellulose derivative within the range of from about 0.05 to about 3 weight percent. In a gel, in which a relatively small amount of water might be used, the cellulose derivative can be the major constituent of the formulation, in some cases, as much as, e.g., about 90 weight percent of the formulation. The important factor is to use at least the minimum amount of cellulose derivative that has a stabilizing effect.

The stabilized compositions of the invention are useful in eye drop formulations, salves for wound healing, gel formulations, foams, and the like. Additional materials such as buffers, preservatives, tonicity adjusting agents, anti-oxidants, other polymers (used, e.g., to adjust viscosity or as extenders), and excipients may be used in the stabilized compositions of the invention. Specific illustrative examples of such other materials include phosphate, citrate, or borate buffers, thimerosal, sorbic acid, methyl or propyl paraben, and chlorobutanol preservatives, sodium chloride and/or sugars to adjust the tonicity, polyvinyl alcohol, poly(acrylic acid) or salts thereof, polyvinyl pyrrolidone, mannitol, lactose, sucrose, ethylene diamine tetra-acetic acid, and the like.

The concentration of epidermal growth factor in the formulation is usually within the range of from about 0.001 to about 100 micrograms per milliliter of aqueous formulation (that is, either the initial aqueous formulation or a formulation that has been reconsitituted after dehydration).

In the examples reported below, the biological activity of stabilized and unstabilized aqueous epidermal growth factor formulations was assayed by the receptor binding assay method of Savage et al., Analytical Biochem., 111, pages 195 et seq. (1981). Briefly, the receptor binding assay procedure is the following:

The receptor binding assay is based on the ability of human EGF to compete with 125 I-labeled mouse epidermal growth factor for binding sites on human cells. The binding is performed on confluent monolayers of formalin fixed human epidermal carcinoma A431 cells [Ref.--Fabricant et al., Proc. Natl. Acad. Sci. USA, Vol. 74, p. 565 (1977), Haigler et al., Proc. Natl. Acad. Sci. USA, Vol. 75, p. 3317 (1978), and Ullrich et al., Nature, Vol. 309, p. 418 (1984)] which possess 10-50 times more EGF receptors on their surface than most other cell types. Labelled mouse epidermal growth factor (125 I-EGF) obtained from Amersham is used.

Multidishes containing a plurality of wells are used. Each well has a confluent monolayer of the formalin fixed human epidermal carcinoma A431 cells at the bottom. First, into each well is added 80 microliters of PBS diluent (phosphate buffered saline containing 0.1 weight percent bovine serum albumin and 0.2M glycine) containing either known standard epidermal growth factor, the sample to be assayed, or a control containing no epidermal growth factor. Serial dilutions of the standard and sample reagents are usually employed. Next, 20 microliters of the 125 I-EGF of a known activity and concentration in PBS is added to each well. (It is important that the reagent additions be made in the sequence given.) The wells are covered and incubated at 37° C. for about 11/4 to 21/2 hours.

The reaction mixture in each well is aspirated to discard the liquid, each well is washed twice with PBS, and the wash liquid is discarded. One hundred microliters of 0.1N NaOH, 1 weight percent sodium dodecyl sulfate, is added to each well. The wells are incubated at 37° C. for 10 minutes, and then the samples are transferred individually to gamma-ray counter vials. The vial with the sample is placed in the gamma ray counter and the number of gamma rays is counted for one minute. Alternatively, multidishes containing removable wells may be employed, in which case, after the washing step, the entire well is removed and placed in the gamma ray counter for counting.

The counts from a serial dilution of a freshly prepared known EGF standard are plotted as a function of EGF concentration on a log-log graph, with the counts per minute being the Y-axis and the concentration being the X-axis. The counts per minute will be inversely proportional to the concentration of the known epidermal growth factor. The curves found for the unknown samples at known dilutions are compared against the curve for a freshly prepared known standard to determine the concentration of active EGF (in micrograms per milliliter) in each unknown sample. Values obtained from duplicates and serial dilutions are averaged to improve the accuracy.

STABILITY STUDIES

Materials and Methods

Pharmaceutical grade polymers were obtained from the following sources:

Poly(vinyl alcohol)--Gelvatol 40/20--Monsanto ("PVA")

Methylcellulose--Methocel A4M--Dow ("MC")

Hydroxypropyl methylcellulose--Methocel E4M-Dow ("HPMC")

Poly(vinyl pyrrolidone)--Plasdone C15--GAF ("PVP")

Polymer solutions were prepared to give viscosities similar to those currently used in ophthalmic formulations. The solutions also contained 0.01 weight percent thimerosal to inhibit bacterial growth and 0.9 weight percent NaCl to make them isotonic. The solutions were filtered through a 0.2 micron polysulfone filter to sterilize them. The filtered solutions were stored in sterile glass vials. epidermal growth factor produced as described in Bell, WO 85/00369, was added to each vial to give a theoretical concentration of 12 micrograms per milliliter. Two control solutions were also used; one contained epidermal growth factor in pure distilled water, and the other contained epidermal growth factor in distilled water containing only the thimerosal plus NaCl. Table I displays the concentrations and intrinsic viscosities at 25° C. of the four polymer solutions;

              TABLE I______________________________________       Concentration,                   IntrinsicPolymer     wt. %       Viscosity, dl/gm______________________________________PVA         1.4         0.24MC          0.25        6.86HPMC        0.25        6.20PVP         1.4         0.16______________________________________

The epidermal growth factor activities of the six solutions were determined by the receptor binding assay procedure described above for the freshly made solutions, and at 6, 21, and 48 days after preparation. The solutions were stored during the test in the vials at 37° C.

Table II, below, displays the activities (expressed as micrograms of active epidermal growth factor per milliliter) for the six solutions, both as made and at the 6, 21, and 48 day intervals, and the percent of the original activity remaining after 48 days.

                                  TABLE II__________________________________________________________________________RECEPTOR BINDING ACTIVITY                             % of original    ACTIVITIES               activitySolution Day 0 Day 6 Day 21 Day 48                             after 48 days__________________________________________________________________________Water    10.6 ± 1.0          10.5 ± 1.5                10.6 ± 1.2                       6.6 ± 0.5                             62Thimerosal/NaCl    12.3 ± 0.7          15.3 ± 4.0                12.8 ± 1.2                       6.8 ± 2.1                             55PVA      16.1 ± 3.5          14.3 ± 1.1                 4.3 ± 2.4                       7.6 ± 0.4                             47MC       18.6 ± 5          12.3 ± 2.3                --     16.8 ± 0.6                             90HPMC     17.4 ± 6          --    --     21.4 ± 4                             100PVP      12.3 ± 4.0          10.9 ± 0.1                 6.1 ± 0.02                       5.0 ± 1.4                             41__________________________________________________________________________

As can be seen by the results displayed above, the aqueous epidermal growth factor solutions containing the two cellulose derivatives lost none of their biological activity (within experimental error) after storage for 48 days, whereas the others lost approximately one-half of their biological activity after the same period of time.

Claims (12)

What is claimed is:
1. A sterile aqueous medicinal composition containing epidermal growth factor and an amount of a water-soluble cellulose polymer sufficient to stabilize said epidermal growth factor against loss of biological activity.
2. The composition of claim 1 wherein the cellulose polymer is hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, or hydroxypropyl methylcellulose.
3. The composition of claim 1 wherein the epidermal growth factor is human epidermal growth factor.
4. The composition of claim 2 wherein the epidermal growth factor is human epidermal growth factor.
5. A sterile composition comprising a dehydrated derivative of the composition of claim 1.
6. A sterile composition comprising a dehydrated derivative of the composition of claim 2.
7. A sterile composition comprising a dehydrated derivative of the composition of claim 3.
8. A sterile composition comprising a dehydrated derivative of the composition of claim 4.
9. A method for stabilizing an aqueous medicinal composition containing epidermal growth factor as an active ingredient, which method comprises incorporating in said composition an amount of a water-soluble cellulose polymer sufficient to stabilize said epidermal growth factor against loss of biological activity in the presence of moisture.
10. The method of claim 9 wherein said cellulose polymer is hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, or hydroxypropyl methylcellulose.
11. The method of claim 9 wherein said epidermal growth factor is human epidermal growth factor.
12. The method of claim 10 wherein said epidermal growth factor is human epidermal growth factor.
US06927627 1986-11-05 1986-11-05 Stabilized compositions containing epidermal growth factor Expired - Lifetime US4717717A (en)

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US06927627 US4717717A (en) 1986-11-05 1986-11-05 Stabilized compositions containing epidermal growth factor
CA 550938 CA1322328C (en) 1986-11-05 1987-11-03 Stabilized compositions containing epidermal growth factor
EP19870309748 EP0267015B1 (en) 1986-11-05 1987-11-04 Stabilized compositions containing epidermal growth factor
DE19873781509 DE3781509T2 (en) 1986-11-05 1987-11-04 Stabilized compositions with contentfresh egf.
DE19873781509 DE3781509D1 (en) 1986-11-05 1987-11-04 Stabilized compositions with contentfresh egf.
ES87309748T ES2044952T3 (en) 1986-11-05 1987-11-04 stabilized compositions containing epidermal growth factor.
DK579787A DK579787D0 (en) 1986-11-05 1987-11-04 Stabilized compositions containing Epidermal Growth Factor
JP27845587A JPS63152324A (en) 1986-11-05 1987-11-05 Epidermis growth factor-containing stabilized composition
JP28314997A JP2942227B2 (en) 1986-11-05 1997-10-01 The pharmaceutical composition for ophthalmic containing epidermal growth factor
JP34989898A JP2988925B2 (en) 1986-11-05 1998-12-09 Medical product comprising a stable composition of biologically active polypeptide

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Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989005149A1 (en) * 1987-12-03 1989-06-15 The Liposome Company, Inc. Methyl cellulose pharmaceutical composition
US4888416A (en) * 1987-03-30 1989-12-19 International Minerals & Chemical Corp. Method for stabilizing somatotropins
US5013714A (en) * 1988-12-15 1991-05-07 Lindstrom Richard L Viscoelastic solution
US5130298A (en) * 1989-05-16 1992-07-14 Ethicon, Inc. Stabilized compositions containing epidermal growth factor
US5158935A (en) * 1989-05-12 1992-10-27 Chiron Corporation Human epidermal growth factor having substitution at position 11
US5189148A (en) * 1989-07-07 1993-02-23 Takeda Chemical Industries, Inc. Stabilized fgf composition and production thereof
US5192743A (en) * 1992-01-16 1993-03-09 Genentech, Inc. Reconstitutable lyophilized protein formulation
US5222978A (en) 1987-08-26 1993-06-29 United States Surgical Corporation Packaged synthetic absorbable surgical elements
US5226912A (en) 1987-08-26 1993-07-13 United States Surgical Corporation Combined surgical needle-braided suture device
WO1993014783A1 (en) * 1992-01-31 1993-08-05 Indu Parikh Growth factor compositions, preparation and use
US5246104A (en) * 1989-08-01 1993-09-21 United States Surgical Corporation Molded suture retainer
US5290920A (en) * 1992-04-16 1994-03-01 Allelix Biopharmaceuticals Inc. Method of purifying human epidermal growth factor
US5306289A (en) * 1987-08-26 1994-04-26 United States Surgical Corporation Braided suture of improved characteristics
US5312642A (en) * 1991-02-08 1994-05-17 United States Surgical Corporation Method and apparatus for calendering and coating/filling sutures
US5314872A (en) * 1988-06-06 1994-05-24 Takeda Chemical Industries, Ltd. Glucan sulfate, stabilized fibroblast growth factor composition
US5359831A (en) 1989-08-01 1994-11-01 United States Surgical Corporation Molded suture retainer
US5360790A (en) * 1990-12-11 1994-11-01 The Regents Of The University Of Michigan Method and formulations for the therapy of acute renal failure
US5366081A (en) 1987-08-26 1994-11-22 United States Surgical Corporation Packaged synthetic absorbable surgical elements
US5411940A (en) * 1993-09-29 1995-05-02 Alcon Laboratories, Inc. Use of TGF-β3 to reduce the formation of scar tissue in response to corneal trauma
ES2070791A1 (en) * 1993-07-05 1995-06-01 Cigb Cosmetic composition for skin care
US5427778A (en) * 1987-09-18 1995-06-27 Ethicon, Inc. Gel formulations containing growth factors and acrylamide polymer
US5457093A (en) * 1987-09-18 1995-10-10 Ethicon, Inc. Gel formulations containing growth factors
US5472702A (en) * 1987-08-26 1995-12-05 United States Surgical Corporation Sterilization of growth factors
US5547935A (en) * 1991-08-16 1996-08-20 Chiron Corporation Muteins of human epidermal growth factor exhibiting enhanced binding at low PH
US5580856A (en) * 1994-07-15 1996-12-03 Prestrelski; Steven J. Formulation of a reconstituted protein, and method and kit for the production thereof
US5693625A (en) * 1989-03-09 1997-12-02 Therapeutiques Substitutives Method of regenerating cells and tissues using functionalized dextrans
US5696091A (en) * 1993-09-29 1997-12-09 Alcon Laboratories, Inc. Use of growth factor and antimetabolite combination to prevent or retard secondary cataract formation
US5705485A (en) * 1987-09-18 1998-01-06 Ethicon, Inc. Gel formulations containing growth factors
US5770228A (en) * 1991-11-04 1998-06-23 Zymogenetics, Inc. Platelet derived growth factor gel formulation
US5894018A (en) * 1993-12-09 1999-04-13 Centro De Immunologia Molecular Vaccine composition comprising autologous epidermal growth factor or a fragment or a derivative thereof having anti-tumor activity and use thereof in the therapy of malignant diseases
US5945402A (en) * 1988-02-26 1999-08-31 Genetech, Inc. Human relaxin formulation
US6054122A (en) * 1990-11-27 2000-04-25 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US6117425A (en) * 1990-11-27 2000-09-12 The American National Red Cross Supplemented and unsupplemented tissue sealants, method of their production and use
US6197325B1 (en) 1990-11-27 2001-03-06 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
WO2001062276A1 (en) * 2000-02-21 2001-08-30 Daewoong Pharm. Co., Ltd. A stable composition comprising epidermal growth factor as an active ingredient
US6399091B1 (en) 1999-06-04 2002-06-04 Lts Lohamann Therapie-Systeme Ag Wound dressing for the controlled release of active substance to wounds, and process for its manufacture
US6559119B1 (en) 1990-11-27 2003-05-06 Loyola University Of Chicago Method of preparing a tissue sealant-treated biomedical material
US6645495B1 (en) * 1997-08-29 2003-11-11 Antigenics, Inc. Compositions of saponin adjuvants and excipients
US6648911B1 (en) 2000-11-20 2003-11-18 Avantec Vascular Corporation Method and device for the treatment of vulnerable tissue site
US6762336B1 (en) 1998-01-19 2004-07-13 The American National Red Cross Hemostatic sandwich bandage
US6818613B2 (en) 2001-11-07 2004-11-16 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
US20050032162A1 (en) * 2003-04-17 2005-02-10 Coco Wayne M. Epidermal growth factor agonists and methods of use
US20060155234A1 (en) * 2002-09-10 2006-07-13 American National Red Cross Hemostatic dressing
USRE39192E1 (en) * 1990-11-27 2006-07-18 American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
USRE39298E1 (en) * 1990-11-27 2006-09-19 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
USRE39321E1 (en) * 1990-11-27 2006-10-03 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US20060251654A1 (en) * 2001-04-12 2006-11-09 Centro De Inmunologia Molecular Method for treatment of malignant and infectious chronic diseases
US20060263355A1 (en) * 2005-02-28 2006-11-23 Joanne Quan Treatment of bone disorders
US7189410B1 (en) 1990-11-27 2007-03-13 The American National Red Cross Supplemented and unsupplemented tissue sealants, methods of their production and use
US7196054B1 (en) 1990-11-27 2007-03-27 The American National Red Cross Methods for treating wound tissue and forming a supplemented fibrin matrix
WO2007034320A2 (en) 2005-09-26 2007-03-29 Adocia Pdgf amphiphilic polymer complex
US20080031934A1 (en) * 2006-08-04 2008-02-07 Macphee Martin Processes for the production of solid dressings for treating wounded tissue
US20090192554A1 (en) * 2008-01-29 2009-07-30 Confluent Surgical, Inc. Bioabsorbable block copolymer
US20100035809A1 (en) * 2006-10-09 2010-02-11 Daewoong Co., Ltd. Stable liquid compositions for treating stomatitis comprising epidermal growth factor
US20110196421A1 (en) * 2007-08-06 2011-08-11 Macphee Martin Methods and dressings for sealing internal injuries
WO2014145016A2 (en) 2013-03-15 2014-09-18 Genentech, Inc. Il-22 polypeptides and il-22 fc fusion proteins and methods of use
US20150352049A1 (en) * 2013-01-30 2015-12-10 Daewoong Co., Ltd. Pharmaceutical composition for protecting wounds, providing hemostasis, or preventing adhesion in the gastrointestinal tract
ES2568517A1 (en) * 2014-10-29 2016-04-29 Fundación Para La Investigación Biomédica Del Hospital Gregorio Marañón Composition for controlled release of compounds

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3883497A (en) * 1972-11-29 1975-05-13 Ici Ltd Polypeptides from urogastrone
US3948875A (en) * 1973-11-27 1976-04-06 Stanley Cohen Process for the preparation of epidermal growth factor and new derivative using cross-linked polyacrylamide gel at a pH of 1-3
US4188375A (en) * 1976-09-25 1980-02-12 Bayer Aktiengesellschaft Process for the preparation of vaccines
US4373519A (en) * 1981-06-26 1983-02-15 Minnesota Mining And Manufacturing Company Composite wound dressing
WO1985000369A1 (en) * 1983-07-05 1985-01-31 Chiron Corporation Hybrid dna synthesis of epidermal growth factor
US4528186A (en) * 1982-06-15 1985-07-09 Japan Chemical Research Co., Ltd. Method of producing human epidermal growth factor
US4621052A (en) * 1980-12-11 1986-11-04 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Process for the production of human epidermal growth factor

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3883497A (en) * 1972-11-29 1975-05-13 Ici Ltd Polypeptides from urogastrone
US3948875A (en) * 1973-11-27 1976-04-06 Stanley Cohen Process for the preparation of epidermal growth factor and new derivative using cross-linked polyacrylamide gel at a pH of 1-3
US4188375A (en) * 1976-09-25 1980-02-12 Bayer Aktiengesellschaft Process for the preparation of vaccines
US4621052A (en) * 1980-12-11 1986-11-04 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Process for the production of human epidermal growth factor
US4373519A (en) * 1981-06-26 1983-02-15 Minnesota Mining And Manufacturing Company Composite wound dressing
US4528186A (en) * 1982-06-15 1985-07-09 Japan Chemical Research Co., Ltd. Method of producing human epidermal growth factor
WO1985000369A1 (en) * 1983-07-05 1985-01-31 Chiron Corporation Hybrid dna synthesis of epidermal growth factor

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
Arakawa et al., Biochemistry, 21, 6536 6544 (1982). *
Arakawa et al., Biochemistry, 21, 6536-6544 (1982).
Carpenter et al., Experimental Cell Research 164, 1 10 (1986). *
Carpenter et al., Experimental Cell Research 164, 1-10 (1986).
Lawn et al., Cell, 15, 1157 1174 (1978). *
Lawn et al., Cell, 15, 1157-1174 (1978).
Savage et al., J. Biol. Chemistry, 247, 7612 7621 (1972). *
Savage et al., J. Biol. Chemistry, 247, 7612-7621 (1972).
Urdea et al., Proc. Natl. Acad. Sci. USA, 80, 7461 7465 (1983). *
Urdea et al., Proc. Natl. Acad. Sci. USA, 80, 7461-7465 (1983).

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4888416A (en) * 1987-03-30 1989-12-19 International Minerals & Chemical Corp. Method for stabilizing somatotropins
US5306289A (en) * 1987-08-26 1994-04-26 United States Surgical Corporation Braided suture of improved characteristics
US5472702A (en) * 1987-08-26 1995-12-05 United States Surgical Corporation Sterilization of growth factors
US5468252A (en) 1987-08-26 1995-11-21 United States Surgical Corporation Packaged synthetic absorbable surgical elements
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US5226912A (en) 1987-08-26 1993-07-13 United States Surgical Corporation Combined surgical needle-braided suture device
US5427778A (en) * 1987-09-18 1995-06-27 Ethicon, Inc. Gel formulations containing growth factors and acrylamide polymer
US5457093A (en) * 1987-09-18 1995-10-10 Ethicon, Inc. Gel formulations containing growth factors
US5705485A (en) * 1987-09-18 1998-01-06 Ethicon, Inc. Gel formulations containing growth factors
WO1989005149A1 (en) * 1987-12-03 1989-06-15 The Liposome Company, Inc. Methyl cellulose pharmaceutical composition
US5945402A (en) * 1988-02-26 1999-08-31 Genetech, Inc. Human relaxin formulation
US5314872A (en) * 1988-06-06 1994-05-24 Takeda Chemical Industries, Ltd. Glucan sulfate, stabilized fibroblast growth factor composition
US5013714A (en) * 1988-12-15 1991-05-07 Lindstrom Richard L Viscoelastic solution
US5693625A (en) * 1989-03-09 1997-12-02 Therapeutiques Substitutives Method of regenerating cells and tissues using functionalized dextrans
US5158935A (en) * 1989-05-12 1992-10-27 Chiron Corporation Human epidermal growth factor having substitution at position 11
US5130298A (en) * 1989-05-16 1992-07-14 Ethicon, Inc. Stabilized compositions containing epidermal growth factor
US5189148A (en) * 1989-07-07 1993-02-23 Takeda Chemical Industries, Inc. Stabilized fgf composition and production thereof
US5246104A (en) * 1989-08-01 1993-09-21 United States Surgical Corporation Molded suture retainer
US5359831A (en) 1989-08-01 1994-11-01 United States Surgical Corporation Molded suture retainer
US5434135A (en) * 1990-08-02 1995-07-18 Indu Parikh Growth factor compositions, preparation and use
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US5540773A (en) * 1991-02-08 1996-07-30 United States Surgical Corporation Apparatus for calendering and coating/filling sutures
US5312642A (en) * 1991-02-08 1994-05-17 United States Surgical Corporation Method and apparatus for calendering and coating/filling sutures
US5447100A (en) * 1991-02-08 1995-09-05 United States Surgical Corporation Apparatus for calendering sutures in orthogonal directions
US5547935A (en) * 1991-08-16 1996-08-20 Chiron Corporation Muteins of human epidermal growth factor exhibiting enhanced binding at low PH
US6191106B1 (en) 1991-08-16 2001-02-20 Chiron Corporation Muteins of epidermal growth factor exhibiting enhanced binding at low pH
US5770228A (en) * 1991-11-04 1998-06-23 Zymogenetics, Inc. Platelet derived growth factor gel formulation
US5192743A (en) * 1992-01-16 1993-03-09 Genentech, Inc. Reconstitutable lyophilized protein formulation
WO1993014783A1 (en) * 1992-01-31 1993-08-05 Indu Parikh Growth factor compositions, preparation and use
US5290920A (en) * 1992-04-16 1994-03-01 Allelix Biopharmaceuticals Inc. Method of purifying human epidermal growth factor
ES2070791A1 (en) * 1993-07-05 1995-06-01 Cigb Cosmetic composition for skin care
US5696091A (en) * 1993-09-29 1997-12-09 Alcon Laboratories, Inc. Use of growth factor and antimetabolite combination to prevent or retard secondary cataract formation
US5411940A (en) * 1993-09-29 1995-05-02 Alcon Laboratories, Inc. Use of TGF-β3 to reduce the formation of scar tissue in response to corneal trauma
US5894018A (en) * 1993-12-09 1999-04-13 Centro De Immunologia Molecular Vaccine composition comprising autologous epidermal growth factor or a fragment or a derivative thereof having anti-tumor activity and use thereof in the therapy of malignant diseases
US5580856A (en) * 1994-07-15 1996-12-03 Prestrelski; Steven J. Formulation of a reconstituted protein, and method and kit for the production thereof
US6645495B1 (en) * 1997-08-29 2003-11-11 Antigenics, Inc. Compositions of saponin adjuvants and excipients
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US20030050238A1 (en) * 2000-02-21 2003-03-13 Jeong-Hwa Yang Stable composition comprising epidermal growth factor as an active ingredient
WO2001062276A1 (en) * 2000-02-21 2001-08-30 Daewoong Pharm. Co., Ltd. A stable composition comprising epidermal growth factor as an active ingredient
US20050186280A1 (en) * 2000-02-21 2005-08-25 Daewoong Pharm. Co., Ltd. Method for stabilizing a composition having a biologically active epidermal growth factor as an active ingredient
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